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Oxidative Stress and Hypoxia in the Pathogenesis of Diabetic Nephropathy

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Studies on Renal Disorders

Abstract

The etiology of diabetic nephropathy is presently not fully understood, and several pathophysiological mechanisms are likely to be involved. However, there is a fair amount of support for a central role of oxidative stress and subsequent tissue hypoxia for the development of diabetes-induced kidney damage. This chapter will summarize some of the major biochemical pathways activated in the diabetic kidney and discuss how these are related to increased oxidative stress, tissue hypoxia, and the progression of diabetic nephropathy.

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References

  1. Najafian B, Mauer M. Progression of diabetic nephropathy in type 1 diabetic patients. Diabetes Res Clin Pract 2009; 83:1–8.

    Article  CAS  PubMed  Google Scholar 

  2. Mogensen CE. Glomerular filtration rate and renal plasma flow in normal and diabetic man during elevation of blood sugar levels. Scand J Clin Lab Invest 1971; 28:177–182.

    Article  CAS  PubMed  Google Scholar 

  3. Palm F, Liss P, Fasching A, Hansell P, Carlsson PO. Transient glomerular hyperfiltration in the streptozotocin-diabetic Wistar Furth rat. Ups J Med Sci 2001; 106:175–182.

    Article  CAS  PubMed  Google Scholar 

  4. Edlund J, Hansell P, Fasching A, Liss P, Weis J, Glickson JD, Palm F. Reduced oxygenation in diabetic rat kidneys measured by T2* weighted magnetic resonance micro-imaging. Adv Exp Med Biol 2009; 645:199–204.

    Article  PubMed  Google Scholar 

  5. Korner A, Eklof AC, Celsi G, Aperia A. Increased renal metabolism in diabetes. Mechanism and functional implications. Diabetes 1994; 43:629–633.

    Article  CAS  PubMed  Google Scholar 

  6. dos Santos EA, Li LP, Ji L, Prasad PV. Early changes with diabetes in renal medullary hemodynamics as evaluated by fiberoptic probes and BOLD magnetic resonance imaging. Invest Radiol 2007; 42:157–162.

    Article  PubMed  Google Scholar 

  7. Rosenberger C, Khamaisi M, Abassi Z, Shilo V, Weksler-Zangen S, Goldfarb M, Shina A, Zibertrest F, Eckardt KU, Rosen S, Heyman SN. Adaptation to hypoxia in the diabetic rat kidney. Kidney Int 2008; 73:34–42.

    Article  CAS  PubMed  Google Scholar 

  8. O’Bryan GT, Hostetter TH. The renal hemodynamic basis of diabetic nephropathy. Semin Nephrol 1997; 17:93–100.

    PubMed  Google Scholar 

  9. Palm F, Cederberg J, Hansell P, Liss P, Carlsson PO. Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension. Diabetologia 2003; 46:1153–1160.

    Article  CAS  PubMed  Google Scholar 

  10. Palm F, Hansell P, Ronquist G, Waldenstrom A, Liss P, Carlsson PO. Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats. Diabetologia 2004; 47:1223–1231.

    Article  CAS  PubMed  Google Scholar 

  11. Thaysen JH, Lassen NA, Munck O. Sodium transport and oxygen consumption in the mammalian kidney. Nature 1961; 190:919–921.

    Article  CAS  PubMed  Google Scholar 

  12. Cohen J, Kamm D. Renal metabolism: Relation to renal function. In: Brenner B, Rector F, eds. The Kidney. Philadelphia: W.B. Saunders, 1985:144–248.

    Google Scholar 

  13. Leonhardt KO, Landes RR. Oxygen tension of the urine and renal structures. Preliminary report of clinical findings. N Engl J Med 1963; 269:115–121.

    Article  CAS  PubMed  Google Scholar 

  14. Klahr S, Hammarman M. Renal metabolism. In Seldin DW, Giebisch G, eds. The Kidney: Physiology and Pathophysiology. New York: Raven Press, 1985:699–718.

    Google Scholar 

  15. Chou SY, Porush JG, Faubert PF. Renal medullary circulation: hormonal control. Kidney Int 1990; 37:1–13.

    Article  CAS  PubMed  Google Scholar 

  16. Aukland K, Krog J. Renal oxygen tension. Nature 1960; 188:671.

    Article  CAS  PubMed  Google Scholar 

  17. Levy MN, Imperial ES. Oxygen shunting in renal cortical and medullary capillaries. Am J Physiol 1961; 200:159–162.

    CAS  PubMed  Google Scholar 

  18. Aukland K. Studies on intrarenal circulation with special reference to gas exchange. J Oslo City Hosp 1964; 14:115–146.

    CAS  PubMed  Google Scholar 

  19. Brezis M, Heyman SN, Dinour D, Epstein FH, Rosen S. Role of nitric oxide in renal medullary oxygenation. Studies in isolated and intact rat kidneys. J Clin Invest 1991; 88:390–395.

    Article  CAS  PubMed  Google Scholar 

  20. Epstein FH. Oxygen and renal metabolism. Kidney Int 1997; 51:381–385.

    Article  CAS  PubMed  Google Scholar 

  21. Schjoedt KJ, Hansen HP, Tarnow L, Rossing P, Parving HH. Long-term prevention of diabetic nephropathy: an audit. Diabetologia 2008; 51:956–961.

    Article  CAS  PubMed  Google Scholar 

  22. Krolewski M, Eggers PW, Warram JH. Magnitude of end-stage renal disease in IDDM: a 35 year follow-up study. Kidney Int 1996; 50:2041–2046.

    Article  CAS  PubMed  Google Scholar 

  23. Nishimura R, Dorman JS, Bosnyak Z, Tajima N, Becker DJ, Orchard TJ. Incidence of ESRD and survival after renal replacement therapy in patients with type 1 diabetes: a report from the Allegheny County Registry. Am J Kidney Dis 2003; 42:117–124.

    Article  PubMed  Google Scholar 

  24. Anon. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993; 329:977–986.

    Google Scholar 

  25. Berg UB, Torbjornsdotter TB, Jaremko G, Thalme B. Kidney morphological changes in relation to long-term renal function and metabolic control in adolescents with IDDM. Diabetologia 1998; 41:1047–1056.

    Article  CAS  PubMed  Google Scholar 

  26. Yip JW, Jones SL, Wiseman MJ, Hill C, Viberti G. Glomerular hyperfiltration in the prediction of nephropathy in IDDM: a 10-year follow-up study. Diabetes 1996; 45:1729–1733.

    Article  CAS  PubMed  Google Scholar 

  27. Brezis M, Rosen S. Hypoxia of the renal medulla – its implication for disease. N Engl J Med 1995; 332:647–655.

    Article  CAS  PubMed  Google Scholar 

  28. Fine LG, Orphanides C, Norman JT. Progressive renal disease: the chronic hypoxia hypothesis. Kidney Int Suppl 1998; 65:S74–S78.

    CAS  PubMed  Google Scholar 

  29. Palm F. Intrarenal oxygen in diabetes and a possible link to diabetic nephropathy. Clin Exp Pharmacol Physiol 2006; 33:997–1001.

    Article  CAS  PubMed  Google Scholar 

  30. Lassen NA, Munck O, Thaysen JH. Oxygen consumption and sodium reabsorption in the kidney. Acta Physiol Scand 1961; 51:371–384.

    Article  CAS  PubMed  Google Scholar 

  31. Thomson SC, Deng A, Bao D, Satriano J, Blantz RC, Vallon V. Ornithine decarboxylase, kidney size, and the tubular hypothesis of glomerular hyperfiltration in experimental diabetes. J Clin Invest 2001; 107:217–224.

    Article  CAS  PubMed  Google Scholar 

  32. Reis JS, Bosco AA, Veloso CA, Mattos RT, Purish S, Nogueira-Machado JA. Oxidizing and reducing responses in type 1 diabetic patients determined up to 5 years after the clinical onset of the disease. Acta Diabetol 2008; 45:221–224.

    Article  CAS  PubMed  Google Scholar 

  33. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000; 404:787–790.

    Article  CAS  PubMed  Google Scholar 

  34. Onozato ML, Tojo A, Goto A, Fujita T, Wilcox CS. Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: Effects of ACEI and ARB. Kidney Int 2002; 61:186–194.

    Article  CAS  PubMed  Google Scholar 

  35. Baines A, Ho P. Glucose stimulates O2 consumption, NOS, and Na/H exchange in diabetic rat proximal tubules. Am J Physiol Renal Physiol 2002; 283:F286–F293.

    CAS  PubMed  Google Scholar 

  36. Peroni O, Large V, Diraison F, Beylot M. Glucose production and gluconeogenesis in postabsorptive and starved normal and streptozotocin-diabetic rats. Metabolism 1997; 46:1358–1363.

    Article  CAS  PubMed  Google Scholar 

  37. Guder WG, Schmolke M, Wirthensohn G. Carbohydrate and lipid metabolism of the renal tubule in diabetes mellitus. Eur J Clin Chem Clin Biochem 1992; 30:669–674.

    CAS  PubMed  Google Scholar 

  38. Schnackenberg CG. Physiological and pathophysiological roles of oxygen radicals in the renal microvasculature. Am J Physiol Regul Integr Comp Physiol 2002; 282:R335–R342.

    CAS  PubMed  Google Scholar 

  39. Gabbay KH, Merola LO, Field RA. Sorbitol pathway: presence in nerve and cord with substrate accumulation in diabetes. Science 1966; 151:209–210.

    Article  CAS  PubMed  Google Scholar 

  40. Williamson JR, Chang K, Frangos M, Hasan KS, Ido Y, Kawamura T, Nyengaard JR, van den Enden M, Kilo C, Tilton RG. Hyperglycemic pseudohypoxia and diabetic complications. Diabetes 1993; 42:801–813.

    Article  CAS  PubMed  Google Scholar 

  41. Shah VO, Dorin RI, Sun Y, Braun M, Zager PG. Aldose reductase gene expression is increased in diabetic nephropathy. J Clin Endocrinol Metab 1997; 82:2294–2298.

    Article  CAS  PubMed  Google Scholar 

  42. Terubayashi H, Sato S, Nishimura C, Kador PF, Kinoshita JH. Localization of aldose and aldehyde reductase in the kidney. Kidney Int 1989; 36:843–851.

    Article  CAS  PubMed  Google Scholar 

  43. Tilton RG, Baier LD, Harlow JE, Smith SR, Ostrow E, Williamson JR. Diabetes-induced glomerular dysfunction: links to a more reduced cytosolic ratio of NADH/NAD+. Kidney Int 1992; 41:778–788.

    Article  CAS  PubMed  Google Scholar 

  44. Dorin RI, Shah VO, Kaplan DL, Vela BS, Zager PG. Regulation of aldose reductase gene expression in renal cortex and medulla of rats. Diabetologia 1995; 38:46–54.

    Article  CAS  PubMed  Google Scholar 

  45. Pugliese G, Tilton RG, Williamson JR. Glucose-induced metabolic imbalances in the pathogenesis of diabetic vascular disease. Diabetes Metab Rev 1991; 7:35–59.

    Article  CAS  PubMed  Google Scholar 

  46. Stevens MJ, Dananberg J, Feldman EL, Lattimer SA, Kamijo M, Thomas TP, Shindo H, Sima AA, Greene DA. The linked roles of nitric oxide, aldose reductase and, (Na+,K+)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat. J Clin Invest 1994; 94:853–859.

    Article  CAS  PubMed  Google Scholar 

  47. Van den Enden MK, Nyengaard JR, Ostrow E, Burgan JH, Williamson JR. Elevated glucose levels increase retinal glycolysis and sorbitol pathway metabolism. Implications for diabetic retinopathy. Invest Ophthalmol Vis Sci 1995; 36:1675–1685.

    PubMed  Google Scholar 

  48. Lajer M, Tarnow L, Fleckner J, Hansen BV, Edwards DG, Parving HH, Boel E. Association of aldose reductase gene Z+2 polymorphism with reduced susceptibility to diabetic nephropathy in Caucasian type 1 diabetic patients. Diabet Med 2004; 21:867–873.

    Article  CAS  PubMed  Google Scholar 

  49. Srivastava SK, Ramana KV, Chandra D, Srivastava S, Bhatnagar A. Regulation of aldose reductase and the polyol pathway activity by nitric oxide. Chem Biol Interact 2003; 143–144:333–340.

    Article  PubMed  CAS  Google Scholar 

  50. Engerman RL, Kern TS, Larson ME. Nerve conduction and aldose reductase inhibition during 5 years of diabetes or galactosaemia in dogs. Diabetologia 1994; 37:141–144.

    Article  CAS  PubMed  Google Scholar 

  51. Kern TS, Engerman RL. Aldose reductase and the development of renal disease in diabetic dogs. J Diabetes Complications 1999; 13:10–16.

    Article  CAS  PubMed  Google Scholar 

  52. Wilcox CS, Welch WJ, Murad F, Gross SS, Taylor G, Levi R, Schmidt HH. Nitric oxide synthase in macula densa regulates glomerular capillary pressure. Proc Natl Acad Sci USA 1992; 89:11993–11997.

    Article  CAS  PubMed  Google Scholar 

  53. Ortiz PA, Garvin JL. Role of nitric oxide in the regulation of nephron transport. Am J Physiol Renal Physiol 2002; 282:F777–F784.

    CAS  PubMed  Google Scholar 

  54. Tojo A, Tisher CC, Madsen KM. Angiotensin II regulates H(+)-ATPase activity in rat cortical collecting duct. Am J Physiol 1994; 267:F1045–F1051.

    CAS  PubMed  Google Scholar 

  55. Welch WJ, Tojo A, Wilcox CS. Roles of NO and oxygen radicals in tubuloglomerular feedback in SHR. Am J Physiol Renal Physiol 2000; 278:F769–F776.

    CAS  PubMed  Google Scholar 

  56. Koivisto A, Matthias A, Bronnikov G, Nedergaard J. Kinetics of the inhibition of mitochondrial respiration by NO. FEBS Lett 1997; 417:75–80.

    Article  CAS  PubMed  Google Scholar 

  57. Koivisto A, Pittner J, Froelich M, Persson AE. Oxygen-dependent inhibition of respiration in isolated renal tubules by nitric oxide. Kidney Int 1999; 55:2368–2375.

    Article  CAS  PubMed  Google Scholar 

  58. Palm F, Teerlink T, Hansell P. Nitric oxide and kidney oxygenation. Curr Opin Nephrol Hypertens 2009; 18:68–73.

    Article  CAS  PubMed  Google Scholar 

  59. Bevers LM, Braam B, Post JA, van Zonneveld AJ, Rabelink TJ, Koomans HA, Verhaar MC, Joles JA. Tetrahydrobiopterin, but not L-arginine, decreases NO synthase uncoupling in cells expressing high levels of endothelial NO synthase. Hypertension 2006; 47:87–94.

    Article  CAS  PubMed  Google Scholar 

  60. Zou MH, Shi C, Cohen RA. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Invest 2002; 109:817–826.

    CAS  PubMed  Google Scholar 

  61. Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, Skatchkov M, Thaiss F, Stahl RA, Warnholtz A, Meinertz T, Griendling K, Harrison DG, Forstermann U, Munzel T. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 2001; 88:E14–E22.

    CAS  PubMed  Google Scholar 

  62. Cai S, Khoo J, Channon KM. Augmented BH4 by gene transfer restores nitric oxide synthase function in hyperglycemic human endothelial cells. Cardiovasc Res 2005; 65:823–831.

    Article  CAS  PubMed  Google Scholar 

  63. Ghafourifar P, Cadenas E. Mitochondrial nitric oxide synthase. Trends Pharmacol Sci 2005; 26:190–195.

    Article  CAS  PubMed  Google Scholar 

  64. Shestakova MV, Vikulova OK, Gorashko NM, Voronko OE, Babunova NB, Nosikov VV, Dedov II. The relationship between genetic and haemodynamic factors in diabetic nephropathy (DN): Case-control study in type 1 diabetes mellitus (T1DM). Diabetes Res Clin Pract 2006; 74(Suppl 1):S41–S50.

    Article  CAS  Google Scholar 

  65. Li B, Yao J, Kawamura K, Oyanagi-Tanaka Y, Hoshiyama M, Morioka T, Gejyo F, Uchiyama M, Oite T. Real-time observation of glomerular hemodynamic changes in diabetic rats: effects of insulin and ARB. Kidney Int 2004; 66:1939–1948.

    Article  CAS  PubMed  Google Scholar 

  66. Hoshiyama M, Li B, Yao J, Harada T, Morioka T, Oite T. Effect of high glucose on nitric oxide production and endothelial nitric oxide synthase protein expression in human glomerular endothelial cells. Nephron Exp Nephrol 2003; 95:e62–e68.

    Article  CAS  PubMed  Google Scholar 

  67. Veelken R, Hilgers KF, Hartner A, Haas A, Bohmer KP, Sterzel RB. Nitric oxide synthase isoforms and glomerular hyperfiltration in early diabetic nephropathy. J Am Soc Nephrol 2000; 11:71–79.

    CAS  PubMed  Google Scholar 

  68. Khamaisi M, Keynan S, Bursztyn M, Dahan R, Reinhartz E, Ovadia H, Raz I. Role of renal nitric oxide synthase in diabetic kidney disease during the chronic phase of diabetes. Nephron Physiol 2006; 102:p72–p80.

    Article  CAS  PubMed  Google Scholar 

  69. Mumtaz FH, Dashwood MR, Khan MA, Thompson CS, Mikhailidis DP, Morgan RJ. Down-regulation of nitric oxide synthase in the diabetic rabbit kidney: potential relevance to the early pathogenesis of diabetic nephropathy. Curr Med Res Opin 2004; 20:1–6.

    Article  CAS  PubMed  Google Scholar 

  70. Du XL, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest 2001; 108:1341–1348.

    CAS  PubMed  Google Scholar 

  71. Komers R, Schutzer WE, Reed JF, Lindsley JN, Oyama TT, Buck DC, Mader SL, Anderson S. Altered endothelial nitric oxide synthase targeting and conformation and caveolin-1 expression in the diabetic kidney. Diabetes 2006; 55:1651–1659.

    Article  CAS  PubMed  Google Scholar 

  72. Komers R, Lindsley JN, Oyama TT, Allison KM, Anderson S. Role of neuronal nitric oxide synthase (NOS1) in the pathogenesis of renal hemodynamic changes in diabetes. Am J Physiol Renal Physiol 2000; 279:F573–F583.

    CAS  PubMed  Google Scholar 

  73. Yagihashi N, Nishida N, Seo HG, Taniguchi N, Yagihashi S. Expression of nitric oxide synthase in macula densa in streptozotocin diabetic rats. Diabetologia 1996; 39:793–799.

    Article  CAS  PubMed  Google Scholar 

  74. Keynan S, Hirshberg B, Levin-Iaina N, Wexler ID, Dahan R, Reinhartz E, Ovadia H, Wollman Y, Chernihovskey T, Iaina A, Raz I. Renal nitric oxide production during the early phase of experimental diabetes mellitus. Kidney Int 2000; 58:740–747.

    Article  CAS  PubMed  Google Scholar 

  75. Maeda M, Yabuki A, Suzuki S, Matsumoto M, Taniguchi K, Nishinakagawa H. Renal lesions in spontaneous insulin-dependent diabetes mellitus in the nonobese diabetic mouse: acute phase of diabetes. Vet Pathol 2003; 40:187–195.

    Article  CAS  PubMed  Google Scholar 

  76. Komers R, Lindsley JN, Oyama TT, Anderson S. Effects of long-term inhibition of neuronal nitric oxide synthase (NOS1) in uninephrectomized diabetic rats. Nitric Oxide 2004; 11:147–155.

    Article  CAS  PubMed  Google Scholar 

  77. Ding Y, Vaziri ND, Coulson R, Kamanna VS, Roh DD. Effects of simulated hyperglycemia, insulin, and glucagon on endothelial nitric oxide synthase expression. Am J Physiol Endocrinol Metab 2000; 279:E11–E17.

    CAS  PubMed  Google Scholar 

  78. Chen H, Brahmbhatt S, Gupta A, Sharma AC. Duration of streptozotocin-induced diabetes differentially affects p38-mitogen-activated protein kinase (MAPK) phosphorylation in renal and vascular dysfunction. Cardiovasc Diabetol 2005; 4:3.

    Article  PubMed  CAS  Google Scholar 

  79. Mensah-Brown EP, Obineche EN, Galadari S, Chandranath E, Shahin A, Ahmed I, Patel SM, Adem A. Streptozotocin-induced diabetic nephropathy in rats: the role of inflammatory cytokines. Cytokine 2005; 31:180–190.

    Article  CAS  PubMed  Google Scholar 

  80. Prabhakar SS. Inhibition of mesangial iNOS by reduced extracellular pH is associated with uncoupling of NADPH oxidation. Kidney Int 2002; 61:2015–2024.

    Article  CAS  PubMed  Google Scholar 

  81. Nakanishi K, Onuma S, Higa M, Nagai Y, Inokuchi T. The intrarenal blood flow distribution and role of nitric oxide in diabetic rats. Metabolism 2005; 54:788–792.

    Article  CAS  PubMed  Google Scholar 

  82. Bank N, Aynedjian HS. Role of EDRF (nitric oxide) in diabetic renal hyperfiltration. Kidney Int 1993; 43:1306–1312.

    Article  CAS  PubMed  Google Scholar 

  83. Komers R, Allen TJ, Cooper ME. Role of endothelium-derived nitric oxide in the pathogenesis of the renal hemodynamic changes of experimental diabetes. Diabetes 1994; 43:1190–1197.

    Article  CAS  PubMed  Google Scholar 

  84. Palm F, Buerk DG, Carlsson PO, Hansell P, Liss P. Reduced nitric oxide concentration in the renal cortex of streptozotocin-induced diabetic rats: effects on renal oxygenation and microcirculation. Diabetes 2005; 54:3282–3287.

    Article  CAS  PubMed  Google Scholar 

  85. Wang YX, Brooks DP, Edwards RM. Attenuated glomerular cGMP production and renal vasodilation in streptozotocin-induced diabetic rats. Am J Physiol 1993; 264:R952–R956.

    CAS  PubMed  Google Scholar 

  86. Komers R, Anderson S. Paradoxes of nitric oxide in the diabetic kidney. Am J Physiol Renal Physiol 2003; 284:F1121–F1137.

    CAS  PubMed  Google Scholar 

  87. Pflueger AC, Larson TS, Hagl S, Knox FG. Role of nitric oxide in intrarenal hemodynamics in experimental diabetes mellitus in rats. Am J Physiol 1999; 277:R725–R733.

    CAS  PubMed  Google Scholar 

  88. Tesfamariam B. Free radicals in diabetic endothelial cell dysfunction. Free Radic Biol Med 1994; 16:383–391.

    Article  CAS  PubMed  Google Scholar 

  89. Schnackenberg CG, Wilcox CS. The SOD mimetic tempol restores vasodilation in afferent arterioles of experimental diabetes. Kidney Int 2001; 59:1859–1864.

    Article  CAS  PubMed  Google Scholar 

  90. Modlinger PS, Wilcox CS, Aslam S. Nitric oxide, oxidative stress, and progression of chronic renal failure. Semin Nephrol 2004; 24:354–365.

    Article  CAS  PubMed  Google Scholar 

  91. Dallinger S, Sieder A, Strametz J, Bayerle-Eder M, Wolzt M, Schmetterer L. Vasodilator effects of L-arginine are stereospecific and augmented by insulin in humans. Am J Physiol Endocrinol Metab 2003; 284:E1106–E1111.

    CAS  PubMed  Google Scholar 

  92. Romero MJ, Iddings J, Platt D, Caldwell RB, Caldwell RW. Diabetes-induced arginase activity contributes to vascular and renal fibrosis and dysfunction. FASEB J 2008; 22:643.

    Google Scholar 

  93. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992; 339:572–575.

    Article  CAS  PubMed  Google Scholar 

  94. Baylis C. Arginine, arginine analogs and nitric oxide production in chronic kidney disease. Nat Clin Pract Nephrol 2006; 2:209–220.

    Article  CAS  PubMed  Google Scholar 

  95. Durban E, Lee HW, Kim S, Paik WK. Purification and characterization of protein methylase I (S-adenosylmethionine: protein-arginine methyltransferase; EC 2.1.1.23) from calf brain. Methods Cell Biol 1978; 19:59–67.

    Article  CAS  PubMed  Google Scholar 

  96. Closs EI, Basha FZ, Habermeier A, Forstermann U. Interference of L-arginine analogues with L-arginine transport mediated by the y+ carrier hCAT-2B. Nitric Oxide 1997; 1:65–73.

    Article  CAS  PubMed  Google Scholar 

  97. Abhary S, Kasmeridis N, Burdon KP, Kuot A, Whiting MJ, Yu WP, Petrovsky N, Craig JE. Diabetic retinopathy is associated with elevated serum asymmetric and symmetric dimethylarginines. Diabetes Care 2009; 32(11):2084–2086.

    Article  CAS  PubMed  Google Scholar 

  98. Kielstein JT, Boger RH, Bode-Boger SM, Frolich JC, Haller H, Ritz E, Fliser D. Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease. J Am Soc Nephrol 2002; 13:170–176.

    CAS  PubMed  Google Scholar 

  99. Tarnow L, Hovind P, Teerlink T, Stehouwer CD, Parving HH. Elevated plasma asymmetric dimethylarginine as a marker of cardiovascular morbidity in early diabetic nephropathy in type 1 diabetes. Diabetes Care 2004; 27:765–769.

    Article  CAS  PubMed  Google Scholar 

  100. Onozato ML, Tojo A, Leiper J, Fujita T, Palm F, Wilcox CS. Expression of NG,NG-dimethylarginine dimethylaminohydrolase and protein arginine N-methyltransferase isoforms in diabetic rat kidney: effects of angiotensin II receptor blockers. Diabetes 2008; 57:172–180.

    Article  CAS  PubMed  Google Scholar 

  101. Chan NN, Chan JC. Asymmetric dimethylarginine (ADMA): a potential link between endothelial dysfunction and cardiovascular diseases in insulin resistance syndrome? Diabetologia 2002; 45:1609–1616.

    Article  CAS  PubMed  Google Scholar 

  102. Sydow K, Mondon CE, Schrader J, Konishi H, Cooke JP. Dimethylarginine dimethylaminohydrolase overexpression enhances insulin sensitivity. Arterioscler Thromb Vasc Biol 2008; 28:692–697.

    Article  CAS  PubMed  Google Scholar 

  103. Xiong Y, Lei M, Fu S, Fu Y. Effect of diabetic duration on serum concentrations of endogenous inhibitor of nitric oxide synthase in patients and rats with diabetes. Life Sci 2005; 77:149–159.

    Article  CAS  PubMed  Google Scholar 

  104. Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M, Tsuji H, Reaven GM, Cooke JP. Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 2002; 106:987–992.

    Article  CAS  PubMed  Google Scholar 

  105. Mittermayer F, Mayer BX, Meyer A, Winzer C, Pacini G, Wagner OF, Wolzt M, Kautzky-Willer A. Circulating concentrations of asymmetrical dimethyl-L-arginine are increased in women with previous gestational diabetes. Diabetologia 2002; 45:1372–1378.

    Article  CAS  PubMed  Google Scholar 

  106. Sydow K, Mondon CE, Cooke JP. Insulin resistance: potential role of the endogenous nitric oxide synthase inhibitor ADMA. Vasc Med 2005; 10(Suppl 1):S35–S43.

    Article  PubMed  Google Scholar 

  107. Hanai K, Babazono T, Nyumura I, Toya K, Tanaka N, Tanaka M, Ishii A, Iwamoto Y. Asymmetric dimethylarginine is closely associated with the development and progression of nephropathy in patients with type 2 diabetes. Nephrol Dial Transplant 2009; 24:1884–1888.

    Article  CAS  PubMed  Google Scholar 

  108. Lajer M, Tarnow L, Jorsal A, Teerlink T, Parving HH, Rossing P. Plasma concentration of asymmetric dimethylarginine (ADMA) predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy. Diabetes Care 2008; 31:747–752.

    Article  CAS  PubMed  Google Scholar 

  109. Zoccali C, Bode-Boger S, Mallamaci F, Benedetto F, Tripepi G, Malatino L, Cataliotti A, Bellanuova I, Fermo I, Frolich J, Boger R. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 2001; 358:2113–2117.

    Article  CAS  PubMed  Google Scholar 

  110. Anthony S, Leiper J, Vallance P. Endogenous production of nitric oxide synthase inhibitors. Vasc Med 2005; 10(Suppl 1):S3–S9.

    Article  PubMed  Google Scholar 

  111. Ogawa T, Kimoto M, Sasaoka K. Occurrence of a new enzyme catalyzing the direct conversion of NG,NG-dimethyl-L-arginine to L-citrulline in rats. Biochem Biophys Res Commun 1987; 148:671–677.

    Article  CAS  PubMed  Google Scholar 

  112. Ogawa T, Kimoto M, Sasaoka K. Purification and properties of a new enzyme, NG, NG-dimethylarginine dimethylaminohydrolase, from rat kidney. J Biol Chem 1989; 264:10205–10209.

    CAS  PubMed  Google Scholar 

  113. Ogawa T, Kimoto M, Watanabe H, Sasaoka K. Metabolism of NG,NG-and NG, N’G-dimethylarginine in rats. Arch Biochem Biophys 1987; 252:526–537.

    Article  CAS  PubMed  Google Scholar 

  114. Leiper JM, Santa Maria J, Chubb A, MacAllister RJ, Charles IG, Whitley GS, Vallance P. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J 1999; 343(Pt 1):209–214.

    Article  CAS  PubMed  Google Scholar 

  115. Komers R, Oyama TT, Chapman JG, Allison KM, Anderson S. Effects of systemic inhibition of neuronal nitric oxide synthase in diabetic rats. Hypertension 2000; 35:655–661.

    CAS  PubMed  Google Scholar 

  116. Thomson SC, Deng A, Komine N, Hammes JS, Blantz RC, Gabbai FB. Early diabetes as a model for testing the regulation of juxtaglomerular NOS I. Am J Physiol Renal Physiol 2004; 287:F732–F738.

    Article  CAS  PubMed  Google Scholar 

  117. O’Byrne S, Forte P, Roberts LJ, 2nd, Morrow JD, Johnston A, Anggard E, Leslie RD, Benjamin N. Nitric oxide synthesis and isoprostane production in subjects with type 1 diabetes and normal urinary albumin excretion. Diabetes 2000; 49:857–862.

    Article  PubMed  Google Scholar 

  118. Johansson BL, Borg K, Fernqvist-Forbes E, Kernell A, Odergren T, Wahren J. Beneficial effects of C-peptide on incipient nephropathy and neuropathy in patients with type 1 diabetes mellitus. Diabet Med 2000; 17:181–189.

    Article  CAS  PubMed  Google Scholar 

  119. Forst T, Kunt T. Effects of C-peptide on microvascular blood flow and blood hemorheology. Exp Diabesity Res 2004; 5:51–64.

    Article  CAS  PubMed  Google Scholar 

  120. Samnegard B, Jacobson SH, Jaremko G, Johansson BL, Sjoquist M. Effects of C-peptide on glomerular and renal size and renal function in diabetic rats. Kidney Int 2001; 60:1258–1265.

    Article  CAS  PubMed  Google Scholar 

  121. Hansen A, Johansson BL, Wahren J, von Bibra H. C-peptide exerts beneficial effects on myocardial blood flow and function in patients with type 1 diabetes. Diabetes 2002; 51:3077–3082.

    Article  CAS  PubMed  Google Scholar 

  122. Forst T, Kunt T, Pohlmann T, Goitom K, Engelbach M, Beyer J, Pfutzner A. Biological activity of C-peptide on the skin microcirculation in patients with insulin-dependent diabetes mellitus. J Clin Invest 1998; 101:2036–2041.

    Article  CAS  PubMed  Google Scholar 

  123. Johansson BL, Sjoberg S, Wahren J. The influence of human C-peptide on renal function and glucose utilization in type 1 (insulin-dependent) diabetic patients. Diabetologia 1992; 35:121–128.

    Article  CAS  PubMed  Google Scholar 

  124. Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998; 339:69–75.

    Article  CAS  PubMed  Google Scholar 

  125. Huang DY, Richter K, Breidenbach A, Vallon V. Human C-peptide acutely lowers glomerular hyperfiltration and proteinuria in diabetic rats: a dose-response study. Naunyn Schmiedebergs Arch Pharmacol 2002; 365:67–73.

    Article  CAS  PubMed  Google Scholar 

  126. Stridh S, Sallstrom J, Friden M, Hansell P, Nordquist L, Palm F. C-peptide normalizes glomerular filtration rate in hyperfiltrating conscious diabetic rats. Adv Exp Med Biol 2009; 645:219–225.

    Article  CAS  PubMed  Google Scholar 

  127. Forst T, Kunt T, Pfutzner A, Beyer J, Wahren J. New aspects on biological activity of C-peptide in IDDM patients. Exp Clin Endocrinol Diabetes 1998; 106:270–276.

    Article  CAS  PubMed  Google Scholar 

  128. Samnegard B, Jacobson SH, Johansson BL, Ekberg K, Isaksson B, Wahren J, Sjoquist M. C-peptide and captopril are equally effective in lowering glomerular hyperfiltration in diabetic rats. Nephrol Dial Transplant 2004; 19:1385–1391.

    Article  CAS  PubMed  Google Scholar 

  129. Rebsomen L, Pitel S, Boubred F, Buffat C, Feuerstein JM, Raccah D, Vague P, Tsimaratos M. C-peptide replacement improves weight gain and renal function in diabetic rats. Diabetes Metab 2006; 32:223–228.

    Article  CAS  PubMed  Google Scholar 

  130. Nordquist L, Brown RD, Fasching A, Persson P, Palm F. Proinsulin C-peptide reduces diabetes-induced glomerular hyperfiltration via efferent arteriole dilation and inhibition of tubular sodium reabsorption. Am J Physiol Renal Physiol 2009; 297(5):F1265–F1272.

    Article  CAS  PubMed  Google Scholar 

  131. Nordquist L, Stridh S. Effects of proinsulin C-peptide on oxygen transport, uptake and utilization in insulinopenic diabetic subjects – a review. Adv Exp Med Biol 2009; 645:193–198.

    Article  CAS  PubMed  Google Scholar 

  132. Nordquist L, Lai EY, Sjoquist M, Patzak A, Persson AE. Proinsulin C-peptide constricts glomerular afferent arterioles in diabetic mice. A potential renoprotective mechanism. Am J Physiol Regul Integr Comp Physiol 2008; 294:R836–R841.

    CAS  PubMed  Google Scholar 

  133. Al-Mashhadi RH, Skott O, Vanhoutte PM, Hansen PB. Activation of A(2) adenosine receptors dilates cortical efferent arterioles in mouse. Kidney Int 2009; 75:793–799.

    Article  CAS  PubMed  Google Scholar 

  134. Murray RD, Churchill PC. Effects of adenosine receptor agonists in the isolated, perfused rat kidney. Am J Physiol 1984; 247:H343–H348.

    CAS  PubMed  Google Scholar 

  135. Juncos LA, Ito S. Disparate effects of insulin on isolated rabbit afferent and efferent arterioles. J Clin Invest 1993; 92:1981–1985.

    Article  CAS  PubMed  Google Scholar 

  136. Holz FG, Steinhausen M. Renovascular effects of adenosine receptor agonists. Ren Physiol 1987; 10:272–282.

    CAS  PubMed  Google Scholar 

  137. Kamikawa A, Ishii T, Shimada K, Makondo K, Inanami O, Sakane N, Yoshida T, Saito M, Kimura K. Proinsulin C-peptide abrogates type-1 diabetes-induced increase of renal endothelial nitric oxide synthase in rats. Diabetes Metab Res Rev 2008; 24:331–338.

    Article  CAS  PubMed  Google Scholar 

  138. Wahren J, Shafqat J, Johansson J, Chibalin A, Ekberg K, Jornvall H. Molecular and cellular effects of C-peptide – new perspectives on an old peptide. Exp Diabesity Res 2004; 5:15–23.

    Article  CAS  PubMed  Google Scholar 

  139. Johansson J, Ekberg K, Shafqat J, Henriksson M, Chibalin A, Wahren J, Jornvall H. Molecular effects of proinsulin C-peptide. Biochem Biophys Res Commun 2002; 295:1035–1040.

    Article  CAS  PubMed  Google Scholar 

  140. Ohtomo Y, Aperia A, Sahlgren B, Johansson BL, Wahren J. C-peptide stimulates rat renal tubular Na+, K(+)-ATPase activity in synergism with neuropeptide Y. Diabetologia 1996; 39:199–205.

    Article  CAS  PubMed  Google Scholar 

  141. Dinour D, Brezis M. Effects of adenosine on intrarenal oxygenation. Am J Physiol 1991; 261:F787–F791.

    CAS  PubMed  Google Scholar 

  142. Gabriels G, Endlich K, Rahn KH, Schlatter E, Steinhausen M. In vivo effects of diadenosine polyphosphates on rat renal microcirculation. Kidney Int 2000; 57:2476–2484.

    Article  CAS  PubMed  Google Scholar 

  143. Liss P, Carlsson PO, Palm F, Hansell P. Adenosine A1 receptors in contrast media-induced renal dysfunction in the normal rat. Eur Radiol 2004; 14:1297–1302.

    Article  PubMed  Google Scholar 

  144. Awad AS, Huang L, Ye H, Duong ET, Bolton WK, Linden J, Okusa MD. Adenosine A2A receptor activation attenuates inflammation and injury in diabetic nephropathy. Am J Physiol Renal Physiol 2006; 290:F828–F837.

    Article  CAS  PubMed  Google Scholar 

  145. Valladares D, Quezada C, Montecinos P, Concha, II, Yanez AJ, Sobrevia L, San Martin R. Adenosine A(2B) receptor mediates an increase on VEGF-A production in rat kidney glomeruli. Biochem Biophys Res Commun 2008; 366:180–185.

    Article  CAS  PubMed  Google Scholar 

  146. Lai EY, Patzak A, Steege A, Mrowka R, Brown R, Spielmann N, Persson PB, Fredholm BB, Persson AE. Contribution of adenosine receptors in the control of arteriolar tone and adenosine-angiotensin II interaction. Kidney Int 2006; 70:690–698.

    Article  CAS  PubMed  Google Scholar 

  147. Nakamoto H, Ogasawara Y, Kajiya F. Visualisation of the effects of dilazep on rat afferent and efferent arterioles in vivo. Hypertens Res 2008; 31:315–324.

    Article  CAS  PubMed  Google Scholar 

  148. Eppel GA, Ventura S, Evans RG. Regional vascular responses to ATP and ATP analogues in the rabbit kidney in vivo: roles for adenosine receptors and prostanoids. Br J Pharmacol 2006; 149:523–531.

    Article  CAS  PubMed  Google Scholar 

  149. Pflueger AC, Schenk F, Osswald H. Increased sensitivity of the renal vasculature to adenosine in streptozotocin-induced diabetes mellitus rats. Am J Physiol 1995; 269:F529–F535.

    CAS  PubMed  Google Scholar 

  150. Di Noia MA, Van Driesche S, Palmieri F, Yang LM, Quan S, Goodman AI, Abraham NG. Heme oxygenase-1 enhances renal mitochondrial transport carriers and cytochrome C oxidase activity in experimental diabetes. J Biol Chem 2006; 281:15687–15693.

    Article  PubMed  CAS  Google Scholar 

  151. Berryman AM, Maritim AC, Sanders RA, Watkins JB, 3rd. Influence of treatment of diabetic rats with combinations of pycnogenol, beta-carotene, and alpha-lipoic acid on parameters of oxidative stress. J Biochem Mol Toxicol 2004; 18:345–352.

    Article  CAS  PubMed  Google Scholar 

  152. Bach FH. Heme oxygenase-1 as a protective gene. Wien Klin Wochenschr 2002; 114(Suppl 4):1–3.

    CAS  PubMed  Google Scholar 

  153. Koya D, Hayashi K, Kitada M, Kashiwagi A, Kikkawa R, Haneda M. Effects of antioxidants in diabetes-induced oxidative stress in the glomeruli of diabetic rats. J Am Soc Nephrol 2003; 14:S250–S253.

    Article  CAS  PubMed  Google Scholar 

  154. Asaba K, Tojo A, Onozato ML, Goto A, Quinn MT, Fujita T, Wilcox CS. Effects of NADPH oxidase inhibitor in diabetic nephropathy. Kidney Int 2005; 67:1890–1898.

    Article  CAS  PubMed  Google Scholar 

  155. Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes 1991; 40:405–412.

    Article  CAS  PubMed  Google Scholar 

  156. Horie K, Miyata T, Maeda K, Miyata S, Sugiyama S, Sakai H, van Ypersole de Strihou C, Monnier VM, Witztum JL, Kurokawa K. Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions. Implication for glycoxidative stress in the pathogenesis of diabetic nephropathy. J Clin Invest 1997; 100:2995–3004.

    Google Scholar 

  157. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005; 54:1615–1625.

    Article  CAS  PubMed  Google Scholar 

  158. Zou AP, Cowley AW, Jr. Reactive oxygen species and molecular regulation of renal oxygenation. Acta Physiol Scand 2003; 179:233–241.

    Article  CAS  PubMed  Google Scholar 

  159. Nishikawa T, Edelstein D, Brownlee M. The missing link: a single unifying mechanism for diabetic complications. Kidney Int Suppl 2000; 77:S26–S30.

    Article  CAS  PubMed  Google Scholar 

  160. Derubertis FR, Craven PA. Activation of protein kinase C in glomerular cells in diabetes. Mechanisms and potential links to the pathogenesis of diabetic glomerulopathy. Diabetes 1994; 43:1–8.

    Article  CAS  PubMed  Google Scholar 

  161. Ishii H, Koya D, King GL. Protein kinase C activation and its role in the development of vascular complications in diabetes mellitus. J Mol Med 1998; 76:21–31.

    Article  CAS  PubMed  Google Scholar 

  162. Brownlee M. A radical explanation for glucose-induced beta cell dysfunction. J Clin Invest 2003; 112:1788–1790.

    CAS  PubMed  Google Scholar 

  163. Ishii H, Jirousek MR, Koya D, Takagi C, Xia P, Clermont A, Bursell SE, Kern TS, Ballas LM, Heath WF, Stramm LE, Feener EP, King GL. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 1996; 272:728–731.

    Article  CAS  PubMed  Google Scholar 

  164. Craven PA, Studer RK, DeRubertis FR. Impaired nitric oxide-dependent cyclic guanosine monophosphate generation in glomeruli from diabetic rats. Evidence for protein kinase C-mediated suppression of the cholinergic response. J Clin Invest 1994; 93:311–320.

    Article  CAS  PubMed  Google Scholar 

  165. Haneda M, Koya D, Kikkawa R. Cellular mechanisms in the development and progression of diabetic nephropathy: activation of the DAG-PKC-ERK pathway. Am J Kidney Dis 2001; 38:S178–S181.

    Article  CAS  PubMed  Google Scholar 

  166. Yang J, Lane PH, Pollock JS, Carmines PK. PKC-dependent superoxide production by the renal medullary thick ascending limb from diabetic rats. Am J Physiol Renal Physiol 2009; 297(5): F1220–F1228.

    Article  CAS  PubMed  Google Scholar 

  167. Kikkawa R, Koya D, Haneda M. Progression of diabetic nephropathy. Am J Kidney Dis 2003; 41:S19–S21.

    Article  CAS  PubMed  Google Scholar 

  168. Brownlee M, Vlassara H, Cerami A. Measurement of glycosylated amino acids and peptides from urine of diabetic patients using affinity chromatography. Diabetes 1980; 29:1044–1047.

    Article  CAS  PubMed  Google Scholar 

  169. Brownlee M. The pathological implications of protein glycation. Clin Invest Med 1995; 18:275–281.

    CAS  PubMed  Google Scholar 

  170. Brownlee M. Glycation products and the pathogenesis of diabetic complications. Diabetes Care 1992; 15:1835–1843.

    Article  CAS  PubMed  Google Scholar 

  171. Rosca MG, Mustata TG, Kinter MT, Ozdemir AM, Kern TS, Szweda LI, Brownlee M, Monnier VM, Weiss MF. Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation. Am J Physiol Renal Physiol 2005; 289:F420–F430.

    Article  CAS  PubMed  Google Scholar 

  172. Poirier O, Nicaud V, Vionnet N, Raoux S, Tarnow L, Vlassara H, Parving HH, Cambien F. Polymorphism screening of four genes encoding advanced glycation end-product putative receptors. Association study with nephropathy in type 1 diabetic patients. Diabetes 2001; 50:1214–1218.

    Article  CAS  PubMed  Google Scholar 

  173. Miyata T, Izuhara Y. Inhibition of advanced glycation end products: an implicit goal in clinical medicine for the treatment of diabetic nephropathy? Ann N Y Acad Sci 2008; 1126:141–146.

    Article  CAS  PubMed  Google Scholar 

  174. Nakamura S, Makita Z, Ishikawa S, Yasumura K, Fujii W, Yanagisawa K, Kawata T, Koike T. Progression of nephropathy in spontaneous diabetic rats is prevented by OPB-9195, a novel inhibitor of advanced glycation. Diabetes 1997; 46:895–899.

    Article  CAS  PubMed  Google Scholar 

  175. Bolton WK, Cattran DC, Williams ME, Adler SG, Appel GB, Cartwright K, Foiles PG, Freedman BI, Raskin P, Ratner RE, Spinowitz BS, Whittier FC, Wuerth JP. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am J Nephrol 2004; 24:32–40.

    Article  CAS  PubMed  Google Scholar 

  176. Brownlee M, Vlassara H, Kooney A, Ulrich P, Cerami A. Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. Science 1986; 232:1629–1632.

    Article  CAS  PubMed  Google Scholar 

  177. Kolm-Litty V, Sauer U, Nerlich A, Lehmann R, Schleicher ED. High glucose-induced transforming growth factor beta1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells. J Clin Invest 1998; 101:160–169.

    Article  CAS  PubMed  Google Scholar 

  178. Yang X, Su K, Roos MD, Chang Q, Paterson AJ, Kudlow JE. O-linkage of N-acetylglucosamine to Sp1 activation domain inhibits its transcriptional capability. Proc Natl Acad Sci USA 2001; 98:6611–6616.

    Article  CAS  PubMed  Google Scholar 

  179. Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu J, Brownlee M. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA 2000; 97:12222–12226.

    Article  CAS  PubMed  Google Scholar 

  180. Sayeski PP, Kudlow JE. Glucose metabolism to glucosamine is necessary for glucose stimulation of transforming growth factor-alpha gene transcription. J Biol Chem 1996; 271:15237–15243.

    Article  CAS  PubMed  Google Scholar 

  181. Weigert C, Friess U, Brodbeck K, Haring HU, Schleicher ED. Glutamine:fructose-6-phosphate aminotransferase enzyme activity is necessary for the induction of TGF-beta1 and fibronectin expression in mesangial cells. Diabetologia 2003; 46:852–855.

    Article  CAS  PubMed  Google Scholar 

  182. Ziyadeh FN, Sharma K, Ericksen M, Wolf G. Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by autocrine activation of transforming growth factor-beta. J Clin Invest 1994; 93:536–542.

    Article  CAS  PubMed  Google Scholar 

  183. Schleicher ED, Weigert C. Role of the hexosamine biosynthetic pathway in diabetic nephropathy. Kidney Int Suppl 2000; 77:S13–S18.

    Article  CAS  PubMed  Google Scholar 

  184. Staniek K, Nohl H. Are mitochondria a permanent source of reactive oxygen species? Biochim Biophys Acta 2000; 1460:268–275.

    Article  CAS  PubMed  Google Scholar 

  185. St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD. Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 2002; 277:44784–44790.

    Article  CAS  PubMed  Google Scholar 

  186. Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell 2005; 120:483–495.

    Article  CAS  PubMed  Google Scholar 

  187. Brand MD, Buckingham JA, Esteves TC, Green K, Lambert AJ, Miwa S, Murphy MP, Pakay JL, Talbot DA, Echtay KS. Mitochondrial superoxide and aging: uncoupling-protein activity and superoxide production. Biochem Soc Symp 2004; (71):203–213.

    Google Scholar 

  188. Korshunov SS, Skulachev VP, Starkov AA. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett 1997; 416:15–18.

    Article  CAS  PubMed  Google Scholar 

  189. Balaban RS, Mandel LJ. Coupling of aerobic metabolism to active ion transport in the kidney. J Physiol 1980; 304:331–348.

    CAS  PubMed  Google Scholar 

  190. Brand MD. Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp Gerontol 2000; 35:811–820.

    Article  CAS  PubMed  Google Scholar 

  191. Dulloo AG, Samec S. Uncoupling proteins: their roles in adaptive thermogenesis and substrate metabolism reconsidered. Br J Nutr 2001; 86:123–139.

    Article  CAS  PubMed  Google Scholar 

  192. Miwa S, St-Pierre J, Partridge L, Brand MD. Superoxide and hydrogen peroxide production by Drosophila mitochondria. Free Radic Biol Med 2003; 35:938–948.

    Article  CAS  PubMed  Google Scholar 

  193. Jezek P, Zackova M, Rehakova Z, Ruzicka M, Borecky J, Skobisova E, Brucknerova J, Garlid KD, Gimeno RE, Tartaglia LA. Existence of uncoupling protein-2 antigen in isolated mitochondria from various tissues. FEBS Lett 1999; 455:79–82.

    Article  CAS  PubMed  Google Scholar 

  194. Jezek P, Garlid KD. Mammalian mitochondrial uncoupling proteins. Int J Biochem Cell Biol 1998; 30:1163–1168.

    Article  CAS  PubMed  Google Scholar 

  195. Friederich M, Nordquist L, Olerud J, Johansson M, Hansell P, Palm F. Identification and distribution of uncoupling protein isoforms in the normal and diabetic rat kidney. Adv Exp Med Biol 2009; 645:205–212.

    Article  CAS  PubMed  Google Scholar 

  196. Friederich M, Fasching A, Hansell P, Nordquist L, Palm F. Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells. Biochim Biophys Acta 2008; 1777:935–940.

    Article  CAS  PubMed  Google Scholar 

  197. Fleury C, Neverova M, Collins S, Raimbault S, Champigny O, Levi-Meyrueis C, Bouillaud F, Seldin MF, Surwit RS, Ricquier D, Warden CH. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet 1997; 15:269–272.

    Article  CAS  PubMed  Google Scholar 

  198. Friederich M, Olerud J, Fasching A, Liss P, Hansell P, Palm F. Uncoupling protein-2 in diabetic kidneys: increased protein expression correlates to increased non-transport related oxygen consumption. Adv Exp Med Biol 2008; 614:37–43.

    Article  PubMed  Google Scholar 

  199. Skulachev VP. Uncoupling: new approaches to an old problem of bioenergetics. Biochim Biophys Acta 1998; 1363:100–124.

    Article  CAS  PubMed  Google Scholar 

  200. Pi J, Bai Y, Daniel KW, Liu D, Lyght O, Edelstein D, Brownlee M, Corkey BE, Collins S. Persistent oxidative stress due to absence of uncoupling protein 2 associated with impaired pancreatic beta-cell function. Endocrinology 2009; 150:3040–3048.

    Article  CAS  PubMed  Google Scholar 

  201. Negre-Salvayre A, Hirtz C, Carrera G, Cazenave R, Troly M, Salvayre R, Penicaud L, Casteilla L. A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB J 1997; 11:809–815.

    CAS  PubMed  Google Scholar 

  202. Packer L, Witt EH, Tritschler HJ. Alpha-lipoic acid as a biological antioxidant. Free Radic Biol Med 1995; 19:227–250.

    Article  CAS  PubMed  Google Scholar 

  203. Gerbitz KD, Gempel K, Brdiczka D. Mitochondria and diabetes. Genetic, biochemical, and clinical implications of the cellular energy circuit. Diabetes 1996; 45:113–126.

    Article  CAS  PubMed  Google Scholar 

  204. Peragon J, Aranda F, Garcia-Salguero L, Vargas AM, Lupianez JA. Long-term adaptive response to dietary protein of hexose monophosphate shunt dehydrogenases in rat kidney tubules. Cell Biochem Funct 1990; 8:11–17.

    Article  CAS  PubMed  Google Scholar 

  205. Peragon J, Aranda F, Garcia-Salguero L, Corpas FJ, Lupianez JA. Stimulation of rat-kidney hexose monophosphate shunt dehydrogenase activity by chronic metabolic acidosis. Biochem Int 1989; 18:1041–1050.

    CAS  PubMed  Google Scholar 

  206. Peragon J, Aranda F, Garcia-Salguero L, Lupianez JA. Influence of experimental diabetes on the kinetic behaviour of renal cortex hexose monophosphate dehydrogenases. Int J Biochem 1989; 21:689–694.

    Article  CAS  PubMed  Google Scholar 

  207. Haque MZ, Majid DS. Assessment of renal functional phenotype in mice lacking gp91PHOX subunit of NAD(P)H oxidase. Hypertension 2004; 43:335–340.

    Article  CAS  PubMed  Google Scholar 

  208. Rey FE, Cifuentes ME, Kiarash A, Quinn MT, Pagano PJ. Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O(2)(-) and systolic blood pressure in mice. Circ Res 2001; 89:408–414.

    Article  CAS  PubMed  Google Scholar 

  209. Leusen JH, Verhoeven AJ, Roos D. Interactions between the components of the human NADPH oxidase: intrigues in the phox family. J Lab Clin Med 1996; 128:461–476.

    Article  CAS  PubMed  Google Scholar 

  210. Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 2004; 4:181–189.

    Article  CAS  PubMed  Google Scholar 

  211. Sumimoto H, Miyano K, Takeya R. Molecular composition and regulation of the Nox family NAD(P)H oxidases. Biochem Biophys Res Commun 2005; 338:677–686.

    Article  CAS  PubMed  Google Scholar 

  212. Gill PS, Wilcox CS. NADPH oxidases in the kidney. Antioxid Redox Signal 2006; 8:1597–1607.

    Article  CAS  PubMed  Google Scholar 

  213. Chabrashvili T, Tojo A, Onozato ML, Kitiyakara C, Quinn MT, Fujita T, Welch WJ, Wilcox CS. Expression and cellular localization of classic NADPH oxidase subunits in the spontaneously hypertensive rat kidney. Hypertension 2002; 39:269–274.

    Article  CAS  PubMed  Google Scholar 

  214. Mollsten A, Marklund SL, Wessman M, Svensson M, Forsblom C, Parkkonen M, Brismar K, Groop PH, Dahlquist G. A functional polymorphism in the manganese superoxide dismutase gene and diabetic nephropathy. Diabetes 2007; 56:265–269.

    Article  PubMed  CAS  Google Scholar 

  215. Kitiyakara C, Chabrashvili T, Chen Y, Blau J, Karber A, Aslam S, Welch WJ, Wilcox CS. Salt intake, oxidative stress, and renal expression of NADPH oxidase and superoxide dismutase. J Am Soc Nephrol 2003; 14:2775–2782.

    Article  CAS  PubMed  Google Scholar 

  216. Wingler K, Wunsch S, Kreutz R, Rothermund L, Paul M, Schmidt HH. Upregulation of the vascular NAD(P)H-oxidase isoforms Nox1 and Nox4 by the renin-angiotensin system in vitro and in vivo. Free Radic Biol Med 2001; 31:1456–1464.

    Article  CAS  PubMed  Google Scholar 

  217. Chabrashvili T, Kitiyakara C, Blau J, Karber A, Aslam S, Welch WJ, Wilcox CS. Effects of ANG II type 1 and 2 receptors on oxidative stress, renal NADPH oxidase, and SOD expression. Am J Physiol Regul Integr Comp Physiol 2003; 285:R117–R124.

    CAS  PubMed  Google Scholar 

  218. Doi K, Noiri E, Tokunaga K. The association of NAD(P)H oxidase p22phox with diabetic nephropathy is still uncertain: response to Hodgkinson, Millward, and Demaine. Diabetes Care 2004; 27:1518–1519; author reply 1519.

    Google Scholar 

  219. Vaziri ND, Dicus M, Ho ND, Boroujerdi-Rad L, Sindhu RK. Oxidative stress and dysregulation of superoxide dismutase and NADPH oxidase in renal insufficiency. Kidney Int 2003; 63:179–185.

    Article  CAS  PubMed  Google Scholar 

  220. Eid AA, Gorin Y, Fagg BM, Maalouf R, Barnes JL, Block K, Abboud HE. Mechanisms of podocyte injury in diabetes: role of cytochrome P450 and NADPH oxidases. Diabetes 2009; 58:1201–1211.

    Article  CAS  PubMed  Google Scholar 

  221. Etoh T, Inoguchi T, Kakimoto M, Sonoda N, Kobayashi K, Kuroda J, Sumimoto H, Nawata H. Increased expression of NAD(P)H oxidase subunits, NOX4 and p22phox, in the kidney of streptozotocin-induced diabetic rats and its reversibility by interventive insulin treatment. Diabetologia 2003; 46:1428–1437.

    Article  CAS  PubMed  Google Scholar 

  222. Wei XF, Zhou QG, Hou FF, Liu BY, Liang M. Advanced oxidation protein products induce mesangial cell perturbation through PKC-dependent activation of NADPH oxidase. Am J Physiol Renal Physiol 2009; 296:F427–F437.

    Article  CAS  PubMed  Google Scholar 

  223. Block K, Gorin Y, Abboud HE. Subcellular localization of Nox4 and regulation in diabetes. Proc Natl Acad Sci U S A 2009; 106:14385–14390.

    Article  CAS  PubMed  Google Scholar 

  224. Kartha GK, Moshal KS, Sen U, Joshua IG, Tyagi N, Steed MM, Tyagi SC. Renal mitochondrial damage and protein modification in type-2 diabetes. Acta Diabetol 2008; 45:75–81.

    Article  CAS  PubMed  Google Scholar 

  225. Touyz RM, Yao G, Viel E, Amiri F, Schiffrin EL. Angiotensin II and endothelin-1 regulate MAP kinases through different redox-dependent mechanisms in human vascular smooth muscle cells. J Hypertens 2004; 22:1141–1149.

    Article  CAS  PubMed  Google Scholar 

  226. Wilcox CS. Oxidative stress and nitric oxide deficiency in the kidney: a critical link to hypertension? Am J Physiol Regul Integr Comp Physiol 2005; 289:R913–R935.

    CAS  PubMed  Google Scholar 

  227. Craven PA, Studer RK, Negrete H, DeRubertis FR. Protein kinase C in diabetic nephropathy. J Diabetes Complications 1995; 9:241–245.

    Article  CAS  PubMed  Google Scholar 

  228. Brands MW, Fitzgerald SM. Arterial pressure control at the onset of type I diabetes: the role of nitric oxide and the renin-angiotensin system. Am J Hypertens 2001; 14:126S–131S.

    Article  CAS  PubMed  Google Scholar 

  229. Deinum J, Tarnow L, van Gool JM, de Bruin RA, Derkx FH, Schalekamp MA, Parving HH. Plasma renin and prorenin and renin gene variation in patients with insulin-dependent diabetes mellitus and nephropathy. Nephrol Dial Transplant 1999; 14:1904–1911.

    Article  CAS  PubMed  Google Scholar 

  230. Kasiske BL, Kalil RS, Ma JZ, Liao M, Keane WF. Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med 1993; 118:129–138.

    CAS  PubMed  Google Scholar 

  231. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345:861–869.

    Article  CAS  PubMed  Google Scholar 

  232. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345:870–878.

    Article  CAS  PubMed  Google Scholar 

  233. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345:851–860.

    Article  CAS  PubMed  Google Scholar 

  234. Nishiyama A, Nakagawa T, Kobori H, Nagai Y, Okada N, Konishi Y, Morikawa T, Okumura M, Meda I, Kiyomoto H, Hosomi N, Mori T, Ito S, Imanishi M. Strict angiotensin blockade prevents the augmentation of intrarenal angiotensin II and podocyte abnormalities in type 2 diabetic rats with microalbuminuria. J Hypertens 2008; 26:1849–1859.

    Article  CAS  PubMed  Google Scholar 

  235. ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 2001; 134:370–379.

    Google Scholar 

  236. Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 1998; 128:982–988.

    CAS  PubMed  Google Scholar 

  237. Benigni A, Colosio V, Brena C, Bruzzi I, Bertani T, Remuzzi G. Unselective inhibition of endothelin receptors reduces renal dysfunction in experimental diabetes. Diabetes 1998; 47:450–456.

    Article  CAS  PubMed  Google Scholar 

  238. Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest 1996; 97:1916–1923.

    Article  CAS  PubMed  Google Scholar 

  239. Pagano PJ, Chanock SJ, Siwik DA, Colucci WS, Clark JK. Angiotensin II induces p67phox mRNA expression and NADPH oxidase superoxide generation in rabbit aortic adventitial fibroblasts. Hypertension 1998; 32:331–337.

    CAS  PubMed  Google Scholar 

  240. Thorp ML. Diabetic nephropathy: common questions. Am Fam Physician 2005; 72:96–99.

    PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from NHLBI (HL-68686), NIDDK (DK-07183, DK-36079, DK-49870, and DK-077858) and from the Swedish Research Council (9940, 72XD-15043 and 10840).

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  1. Department of Medical Cell Biology, Uppsala University, 571751, 23, Uppsala, Sweden

    Fredrik Palm

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  1. Fredrik Palm
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  2. Lina Nordquist
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  3. Christopher S. Wilcox
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  4. Peter Hansell
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Correspondence to Fredrik Palm .

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Editors and Affiliations

  1. Graduate School of Medicine, Division of Molecular Medicine and Thera, Tohoku University, Seiryo-machi 2-1, Sendai, 980-8575, Japan

    Toshio Miyata

  2. Medizinische Klinik IV, Universitätsklinikum Erlangen, Krankenhausstr. 12, Erlangen, 91054, Germany

    Kai-Uwe Eckardt

  3. Graduate School of Medicine &, Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Tokyo, 113-8655, Japan

    Masaomi Nangaku

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Palm, F., Nordquist, L., Wilcox, C.S., Hansell, P. (2011). Oxidative Stress and Hypoxia in the Pathogenesis of Diabetic Nephropathy. In: Miyata, T., Eckardt, KU., Nangaku, M. (eds) Studies on Renal Disorders. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press. https://doi.org/10.1007/978-1-60761-857-7_29

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